Approximately 20.6 % of the general population in the United States smokes cigarettes and this group may be comprised of smokers with severe nicotine dependence who are resistant to smoking cessation pharmacotherapies and treatments (Hughes, 2011). Varenicline is a first-line medication for smoking cessation that has been shown in meta-analytic reviews to be superior to other smoking cessation treatments (Cahill et al., 2010), however 56% of patients who take varenicline do not achieve smoking abstinence. One strategy to increase quit rates may be to administer a complimentary medication to augment the efficacy of varenicline. The anti-epileptic medication zonisamide is a good candidate for adjunct treatment because it increases dopaminergic tone, normalizes glutamate homeostasis, and potentiates GABA release. Zonisamide also improves sleep and promotes weight loss, two prominent issues not addressed by varenicline. Finally, the PI of this proposal has documented unpleasant changes in the taste of cigarettes and reductions in nicotine withdrawal among patients receiving zonisamide for the treatment of cocaine dependence. The proposed study will explore the efficacy of varenicline + zonisamide for smoking cessation using a controlled, clinical trial. Eligible participants (n=60) will be smokers (>10 cigarettes per day or >1 year) seeking treatment. They will be randomly assigned to receive zonisamide + varenicline or placebo + varenicline under double-blind conditions for a 10-week period. Participants will visit the clinic weekly to receive medication and smoking cessation counseling and also to complete self-report ratings of smoking, nicotine withdrawal and other smoking-related indices. Smoking status will be assessed via urinalysis testing for the nicotine metabolite cotinine (<200ng/ml will be considered abstinent) from specimens obtained at each study visit. Cotinine is a sensitive indicator of smoking status with a longer half-life then carbon monoxide (CO) and is therefore more likely to detect low or intermittent smoking. The study hypothesis is that participants who receive the combination zonisamide + varenicline will achieve greater smoking abstinence when compared to varenicline alone. The primary outcome measure for this study will be the 4-week rate of biochemically-confirmed continuous smoking abstinence during weeks 7-10 of the intervention. Secondary outcomes will include self-reported rates of smoking, subjective effects of cigarettes, mean body weight change from baseline to week 10, self-reported sleep quality, and nicotine withdrawal symptom severity. Results from this study will contribute important information on successful and cost-effective smoking cessation interventions for individuals who do not respond optimally to current smoking cessation medications. This study will advance the science and clinical treatment of smoking cessation, and will provide the prerequisite data to develop a larger scale clinical trial evaluation of the combination zonisamide + varenicline for smoking cessation.